CAREER: Developing a Computational Workflow to Quantify Atomic-level Allosteric Mechanisms

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With support from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, and the Established Program to Stimulate Competitive Research (EPSCoR), Martin McCullagh and his research group at Oklahoma State University will develop computational methods and workflows to quantify allosteric response in proteins. Allostery in proteins can switch on and off the primary function through the binding of a molecule at a secondary site on the protein. This behavior serves as important handle for the development of therapeutics as well as the design of novel proteins. The computational workflows developed in the McCullagh group will be used to quantify allosteric response as well as identify new allosteric sites for further regulation of the protein. The McCullagh group will also develop jupyter notebook-based chemistry lessons to both introduce chemistry concepts in a novel way and introduce aspects of coding to undergraduate chemistry students.The McCullagh group will develop and verify a computational workflow to quantify allosteric response and describe the atomic-level details that underlie this behavior. Allostery is the altering of enzyme function at one site due to a perturbation of the enzyme at a distal site. Despite over a century of work on this topic, two key questions remain unanswered: (1) What are the atomic-level changes that contribute to allostery in a complete four-state thermodynamic cycle? (2) Can we harness the atomic-level allosteric mechanisms to identify new targets to impact the observed allostery? This project will address these questions using two pyruvate kinase isozymes as model systems. The K-type allosteric response of these enzymes is a pivotal control valve for the last step in glycolysis. This project will also develop and freely distribute online jupyter notebook-based chemistry lessons.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.